The orphan ligand, activin C, signals through activin receptor-like kinase 7

Activin ligands are formed from two disulfide-linked inhibin beta (Inh beta) subunit chains. They exist as homodimeric proteins, as in the case of activin A (ActA; Inh beta A/Inh beta A) or activin C (ActC; Inh beta C/Inh beta C), or as heterodimers, as with activin AC (ActAC; Inh beta A:Inh beta C). While the biological functions of ActA and activin B (ActB) have been well characterized, little is known about the biological functions of ActC or ActAC. One thought is that the Inh beta C chain functions to interfere with ActA production by forming less active ActAC heterodimers. Here, we assessed and characterized the signaling capacity of ligands containing the Inh beta C chain. ActC and ActAC activated SMAD2/3-dependent signaling via the type I receptor, activin receptor-like kinase 7 (ALK7). Relative to ActA and ActB, ActC exhibited lower affinity for the cognate activin type II receptors and was resistant to neutralization by the extracellular antagonist, follistatin. In mature murine adipocytes, which exhibit high ALK7 expression, ActC elicited a SMAD2/3 response similar to ActB, which can also signal via ALK7. Collectively, these results establish that ActC and ActAC are active ligands that exhibit a distinct signaling receptor and antagonist profile compared to other activins.